A phase 1 study evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of Bcl-2 inhibitor BGB-11417 in adult patients with mature B-cell malignancies.
Authors: Caixia Li, Jia Wei, Keshu Zhou, Peng Liu, He Huang, Fei Li, Qingqing Cai, Yujun Dong, Shenmiao Yang, Hui Zhou, Xinyou Zhang, Lu Zhang, Zaixing Shi, Zhiyu Liang, Binghao Wu, Depei Wu
Journal: Journal of Clinical Oncology (2023)

7558 Background: BGB-11417 is a potent and highly selective Bcl-2 inhibitor. Phase 1 study results showing high activity and good tolerability in patients (pts) with mature B-cell malignancies were previously reported (Abstract 2989, ASH 2022). We present here results of BGB-11417 monotherapy in B-cell malignancies with a longer follow up. Methods: BGB-11417-102 (NCT04883957) is an ongoing, multicenter, phase 1, open-label, dose-finding study in China. Primary objectives: safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of BGB-11417 monotherapy for selected cohorts. Pts with relapsed/refractory (R/R) B-cell malignancies received escalating doses (80, 160, 320, or 640 mg once daily) with weekly or daily ramp-up to intended target dose. Dose-limiting toxicity (DLT) for each cohort was evaluated during ramp-up through day 21 at the intended dose. AEs were reported per CTCAE v5.0 (or Grading Scale for Hematologic Toxicity in chronic lymphocytic leukemia [CLL] Studies). Results: As of 1 Oct 2022, 54 pts (34 R/R non-Hodgkin lymphoma [NHL; 20 diffuse large B-cell lymphoma, 7 follicular lymphoma, 4 marginal zone lymphoma, 3 transformed NHL], and 20 R/R CLL/small lymphocytic lymphoma [SLL]) received ≤640 mg/d. 640mg was the highest dose pre-defined in the study and MTD was not reached. Median (range) values: age, 61 y (31-84); prior lines of systemic therapy, 2 (1-7); follow-up duration, 6.6 m (0.2-13.0). Study discontinuation: 23 pts (22 NHL; 1 CLL/SLL); reasons: 18 progressive disease, 4 withdrew, 1 investigator decision. Tx-emergent AEs (TEAEs): all grades, 92.6%; grade ≥3, 53.7%. Most common TEAE: all grades, white blood cell count decreased (48.1%); grade ≥3, neutropenia (25.9%). DLTs occurred in 3 patients at 80 mg/d or 160 mg/d; 14.8% had serious TEAEs and 14.8% had TEAEs leading to drug interruption. No pts had TEAEs leading to death/tx discontinuation or clinical tumor-lysis syndrome events. Of 39 pts available for tumor assessment (27 NHL; 12 CLL/SLL), 5 with NHL and 9 with CLL/SLL achieved responses (NHL: 3 partial responses [PR] at 160 mg/d, 1 PR at 320 mg/d, 1 complete response [CR] at 640 mg/d; CLL/SLL: 2 CR and 2 PR at 80 mg/d, 3 PR at 160 mg/d, 2 PR at 320 mg/d). Nine pts with R/R CLL/SLL (5 at 80mg/d, 4 at 160 mg/d) had minimum residual disease (MRD) assessment; 3 had undetectable MRD with CLL cell/total nucleated cells &lt; 10 -4 (uMRD4; 1 pt achieved blood and bone marrow aspirate uMRD4 after 4.5 months at 80 mg/d; 2 pts had blood uMRD4 after 7.1 months at 160 mg/d). The monotherapy RP2D for R/R CLL/SLL was 320 mg/d. Conclusions: These results demonstrated that BGB-11417 monotherapy was well tolerated at all tested doses up to 640 mg/d, with no dose-dependent toxicity increase. BGB-11417 monotherapy showed promising initial efficacy results in R/R CLL/SLL, with pts achieving responses at lower dose levels. Clinical trial information: NCT04883957 .